We propose to continue our investigations of the mechanisms by which large molecules are transported across capillary walls, of how they become distributed in the interstitial fluid, and of how they are collected by the lymphatics and returned to the bloodstream. For the period covered by this proposal, we shall concentrate on the following aspects of blood - interstitial fluid - lymph exchange. 1) The coupling of large molecular transport to fluid exchange and its significance for structure-function relations in the capillary endothelium. 2) The distribution of plasma macromolecules in the interstitial space in relation to the structure and properties of the fluid-gel matrix, and to steady state fluid and solute transport rates. 3) The role of changes in capillary permeability and interstitial matrix properties in the control of plasma and interstitial volume in the whole animal. We shall study these phenomena by means of experiments on anesthetized dogs and rats, using endogenous plasma proteins and exogenous proteins, Dextrans and other macromolecules as test substances. Plasma, lymph, and tissue samples will be collected and analyzed, and the results evaluated according to transport theory for multi-pathway membranes. In addition to animal studies, we shall carry out experiments on transport of water and solutes through artificial porous membranes coated or filled with restrictive gels, in order to develop an adequate theory of diffusive and convective transport in such membranes, which provide a better model for the capillary endothelium than simple water-filled pores. The results of our experiments will add to our knowledge of the regulation of plasma and interstitial fluid volume, and contribute to the development of new methods to treat disturbances of extracellular fluid balance.